New Process For The Preparation Of Oxabispidines

ABSTRACT

There is provided a process for the preparation of a compound of formula (I): which process comprises reaction of a compound of formula (TI): with either a compound of formula (ITT): or acrylamide, followed, in the latter case, by reaction of the resulting intermediate of formula (IV): with an alcohol of formula R 2 ═OH and an agent that promotes, or agents that in combination promote, rearrangement and oxidation of the compound of formula IV to an intermediate isocyanate, which may then react with the alcohol of formula R 2 ═OH, and wherein R 1 , R 2  and R 16  have meanings given in the description.

FIELD OF THE INVENTION

This invention relates to a novel process for the preparation ofoxabispidine compounds that bear a N-2-(alkoxycarbonylamino)ethylsubstituent.

PRIOR ART

The number of documented compounds including the9-oxa-3,7-diazabicyclo-[3.3.1]nonane (oxabispidine) structure is veryfew. As a result, there are very few known processes that arespecifically adapted for the preparation of oxabispidine compounds.

Certain oxabispidine compounds are disclosed in Chem. Ber. 96(11), 2827(1963) as intermediates in the synthesis of 1,3-diaza-6-oxa-adamantanes.

Hemiacetals (and related compounds) having the oxabispidine ringstructure are disclosed in J. Org. Chem. 31, 277 (1966), ibid. 61(25),8897 (1996), ibid. 63(5), 1566 (1998) and ibid. 64(3), 960 (1999) asunexpected products from the oxidation of 1,5-diazacyclooctane-1,3-diolsor the reduction of 1,5-diazacyclooctane-1,3-diones.

1,3-Dimethyl-3,7-ditosyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane isdisclosed in J. Org. Chem. 32, 2425 (1967) as a product from theattempted acetylation oftrans-1,3-dimethyl-1,5-ditosyl-1,5-diazacyclooctane-1,3-diol.

None of the above-mentioned documents disclose or suggest the synthesisof oxabispidine compounds that bear a N-2-(alkoxycarbonylamino)ethylsubstituent.

International patent application WO 01/28992 describes the synthesis ofa wide range of oxabispidine compounds, which compounds are indicated asbeing useful in the treatment of cardiac arrhythmias. Amongst thecompounds disclosed are a number that bear aN-2-(tert-butoxycarbonylamino)ethyl substituent. However, there is nodisclosure in WO 01/28992 of processes for introducingN-2-(alkoxycarbonylamino)ethyl substituents into the oxabispidinenucleus that comprise either: (a) nucleophilic substitution of asulfonate group from a 2-(alkoxycarbonylamino)ethyl sulfonate; or (b)reaction with acrylamide, followed by rearrangement of the resultingprimary amide to an isocyanate intermediate, and subsequent reaction ofthat intermediate with an alcohol.

We have now found, surprisingly, that oxabispidine compounds that bear aN-2-(alkoxycarbonylamino)ethyl substituent may be prepared readily fromthe corresponding N-unsubstituted oxabispidines via such processes.

DESCRIPTION OF THE INVENTION

According to a first aspect of the invention there is provided a processfor the preparation of a compound of formula I,

wherein R¹ represents H, an amino protective group or a structuralfragment of formula Ia,

in which

-   -   R represents H, halo, C₁₋₆ alkyl, —OR⁶, -E-N(R⁷)R⁸ or, together        with R⁴, represents=0;    -   R⁴represents H, C₁₋₆ alkyl or, together with R³, represents ═O;    -   R⁶ represents H, C₁₋₆ alkyl, -E-aryl, -E-Het¹, —C(O)R^(9a),        —C(O)OR^(9b) or —C(O)N(R^(10a))R^(10b);    -   R⁷ represents H, C₁₋₆ alkyl, -E-aryl, -E-Het¹, —C(O)R^(9a),        —C(O)OR^(9b), —S(O)₂R^(9c), —[C(O)]_(p)N(R^(10a))R^(10b) or        —C(NH)NH₂;    -   R⁸ represents H, C₁₋₆ alkyl, -E-aryl or —C(O)R^(9d);    -   R^(9a) to R^(9d) independently represent, at each occurrence        when used herein, C₁₋₆ alkyl (optionally substituted and/or        terminated by one or more substituents selected from halo, aryl        and Het²), aryl, Het³, or R^(9a) and R^(9d) independently        represent H;    -   R^(10a) and R^(10b) independently represent, at each occurrence        when used herein, H or C₁₋₆ alkyl (optionally substituted and/or        terminated by one or more substituents selected from halo, aryl        and Het⁴), aryl, Het⁵, or together represent C₃₋₆ alkylene,        optionally interrupted by an O atom;    -   E represents, at each occurrence when used herein, a direct bond        or C₁₋₄ alkylene;    -   p represents 1 or 2;    -   A represents -G-, -J-N(R¹¹)— or -J-O— (in which latter two        groups, N(R¹¹)— or O— is attached to the carbon atom bearing R³        and R⁴);    -   B represents -Z-, -Z-N(R¹²)—, —N(R¹²)-Z-, -Z-S(O)_(n)— or -Z-O—        (in which latter two groups, Z is attached to the carbon atom        bearing R³and R⁴);    -   G represents a direct bond or C₁₋₆ alkylene;    -   J represents C₂₋₆ alkylene;    -   Z represents a direct bond or C₁₋₄ alkylene;    -   R¹¹ and R¹² independently represent H or C₁₋₆ alkyl;    -   n represents 0, 1 or 2;    -   R⁵ represents phenyl or pyridyl, both of which groups are        optionally substituted by one or more substituents selected from        —OH, cyano, halo, nitro, C₁₋₆ alkyl (optionally terminated by        —N(H)C(O)OR^(13a)), C₁₋₆ alkoxy, —N(R^(14a))R^(14b),        C(O)R^(14c), —C(O)OR^(14d),        —C(O)N(R^(14e))R^(14f)—N(R^(14g))C(O)R^(14h),        —N(R^(14i))C(O)N(R^(14j))R^(14k), —N(R^(14m))S(O)₂R^(13b),        —S(O)₂R^(13c) and/or —OS(O)₂R^(13d),    -   R^(13a) to R^(13d) independently represent C₁₋₆ alkyl;    -   R^(14a) and R^(14b) independently represent H, C₁₋₆ alkyl or        together represent C₃₋₆ alkylene, resulting in a four- to        seven-membered nitrogen-containing ring;    -   R^(14c) to R^(14m) independently represent H or C₁₋₆ alkyl; and

Het¹ to Het⁵ independently represent, at each occurrence when usedherein, five- to twelve-membered heterocyclic groups containing one ormore heteroatoms selected from oxygen, nitrogen and/or sulfur, whichheterocyclic groups are optionally substituted by one or moresubstituents selected from ═O, —OH, cyano, halo, nitro, C₁₋₆ alkyl, C₁₋₆alkoxy, aryl, aryloxy, —N(R^(15a))R^(15b), —C(O)R^(15c), —C(O)OR^(15d),—C(O)N(R^(15e))R^(15f), —N(R^(15g))C(O)R^(15h) and—N(R^(15i))S(O)₂R^(15j);

-   -   R^(15a) to R^(15i) independently represent C₁₋₆ alkyl, aryl or        R^(15a) to R^(15i) independently represent H;    -   provided that:    -   (a) when R⁴ represents H or C₁₋₄ alkyl; and        -   A represents -J-N(R¹¹)— or -J-O—;        -   then B does not represent —N(R¹²)—, —S(O)_(n)—, —O— or            —N(R¹²)-Z- (in which latter group —N(R¹²) is attached to the            carbon atom bearing R³ and R⁴);    -   (b) when R³ represents —OR⁶ or -E-N(R⁷)R⁸ in which E represents        a direct bond, then:        -   (i) A does not represent a direct bond, -J-N(R¹¹)— or -J-O—;            and        -   (ii) B does not represent —N(R¹²)—, —S(O)_(n)—, —O— or            —N(R¹²)-Z- (in which latter group —N(R¹²) is attached to the            carbon atom bearing R³ and R⁴); and    -   R² represents C₁₋₆ alkyl (optionally substituted and/or        terminated by one or more substituents selected from —OH, halo,        cyano, nitro and aryl) or aryl,    -   wherein each aryl and aryloxy group, unless otherwise specified,        is optionally substituted;    -   which process comprises reaction of a compound of formula II,    -   wherein R¹ is as defined above, with either:    -   (i) a compound of formula III,        -   wherein R¹⁶ represents unsubstituted C₁₋₄ alkyl, C₁₋₄            perfluoroalkyl or phenyl, which latter group is optionally            substituted by one or more substituents selected from C₁₋₆            alkyl, halo, nitro and C₁₋₆ alkoxy, and R² is as defined            above; or    -   (ii) acrylamide, followed by reaction of the resulting        intermediate of formula IV,        -   wherein R¹ is as defined above, with an alcohol of formula            R²—OH and an agent that promotes, or agents that in            combination promote, rearrangement and oxidation of the            compound of formula IV to an intermediate isocyanate, which            may then react with the alcohol of formula R²—OH, wherein R²            is as defined above,            and which process is referred to hereinafter as “the process            of the invention”.

Unless otherwise specified, alkyl groups and alkoxy groups as definedherein may be straight-chain or, when there is a sufficient number (i.e.a minimum of three) of carbon atoms be branched-chain, and/or cyclic.Further, when there is a sufficient number (i.e. a minimum of four) ofcarbon atoms, such alkyl and alkoxy groups may also be partcyclic/acyclic. Such alkyl and alkoxy groups may also be saturated or,when there is a sufficient number (i.e. a minimum of two) of carbonatoms, be unsaturated and/or interrupted by one or more oxygen and/orsulfur atoms. Unless otherwise specified, alkyl and alkoxy groups mayalso be substituted by one or more halo, and especially fluoro, atoms.

Unless otherwise specified, alkylene groups as defined herein may bestraight-chain or, when there is a sufficient number (i.e. a minimum oftwo) of carbon atoms, be branched-chain. Such alkylene chains may alsobe saturated or, when there is a sufficient number (i.e. a minimum oftwo) of carbon atoms, be unsaturated and/or interrupted by one or moreoxygen and/or sulfur atoms. Unless otherwise specified, alkylene groupsmay also be substituted by one or more halo atoms.

The term “aryl”, when used herein, includes C₆₋₁₀ aryl groups such asphenyl, naphthyl and the like. The term “aryloxy”, when used hereinincludes C₆₋₁₀ aryloxy groups such as phenoxy, naphthoxy and the like.For the avoidance of doubt, aryloxy groups referred to herein areattached to the rest of the molecule via the O-atom of the oxy-group.Unless otherwise specified, aryl and aryloxy groups may be substitutedby one or more substituents including —OH, cyano, halo, nitro, C₁₋₆alkyl, C₁₋₆ alkoxy, —N(R^(14a))R^(14b), —C(O)R^(14c), —C(O)OR^(14d)d,—C(O)N(R^(14e))R^(14f), N(R^(14g))C(O)R^(14h), N(R^(14m))S(O)₂R^(13b),—S(O)₂R^(13c) and/or —OS(O)₂R^(13d) (wherein R^(13b) to R^(13d) andR^(14a) to R^(14m) are as hereinbefore defined). When substituted, aryland aryloxy groups are preferably substituted by between one and threesubstitutents.

The term “halo”, when used herein, includes fluoro, chloro, bromo andiodo.

Het (Het¹ to Het⁵) groups that may be mentioned include those containing1 to 4 heteroatoms (selected from the group oxygen, nitrogen and/orsulfur) and in which the total number of atoms in the ring system arebetween five and twelve. Het (Het¹ to Het⁵) groups may be fullysaturated, wholly aromatic, partly aromatic and/or bicyclic incharacter. Heterocyclic groups that may be mentioned includebenzodioxanyl, benzodioxepanyl, benzodioxolyl, benzofuranyl,benzimidazolyl, benzomorpholinyl, benzoxazinonyl, benzothiophenyl,chromanyl, cinnolinyl, dioxanyl, furanyl, imidazolyl,imidazo[1,2-a]pyridinyl, indolyl, isoquinolinyl, isoxazolyl,morpholinyl, oxazolyl, phthalazinyl, piperazinyl, piperidinyl, purinyl,pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimindinyl, pyrrolidinonyl,pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl,tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, thienyl, thiochromanyl,triazolyl and the like. Substituents on Het (Het¹ to Het⁵) groups may,where appropriate, be located on any atom in the ring system including aheteroatom. The point of attachment of Het (Het¹ to Het⁵) groups may bevia any atom in the ring system including (where appropriate) aheteroatom, or an atom on any fused carbocyclic ring that may be presentas part of the ring system. Het (Het¹ to Het⁵) groups may also be in theN— or S-oxidised form.

As used herein, the term “amino protective group” includes groupsmentioned in “Protective Groups in Organic Synthesis”, 2^(nd) edition, TW Greene & P G M Wutz, Wiley-Interscience (1991), in particular thoseindexed at the start of the chapter entitled “Protection for the AminoGroup” (see pages 309 to 315) of that reference, the disclosure in whichdocument is hereby incorporated by reference.

Specific examples of amino protective groups thus include:

-   -   (a) those which form carbamate groups (e.g. to provide methyl,        cyclopropylmethyl, 1-methyl-1-cyclopropylmethyl,        diisopropylmethyl, 9-fluorenylmethyl,        9-(2-sulfo)fluorenylmethyl, 2-furanylmethyl,        2,2,2-trichloroethyl, 2-haloethyl, 2-trimethylsilylethyl,        2-methylthioethyl, 2-methylsulfonylethyl,        2(p-toluenesulfonyl)ethyl, 2-phosphonioethyl,        1,1-dimethylpropynyl,        1,1-dimethyl-3-(N,N-dimethylcarboxamido)-propyl,        1,1-dimethyl-3-(N,N-diethylamino)-propyl,        1-methyl-1-(1-adamantyl)ethyl, 1-methyl-1-phenylethyl,        1-methyl-1-(3,5-dimethoxyphenyl)ethyl,        1-methyl-1-(4-biphenylyl)-ethyl,        1-methyl-1-(p-phenylazophenyl)ethyl, 1,1-dimethyl-2-haloethyl,        1,1-dimethyl-2,2,2-trichloroethyl, 1,1-dimethyl-2-cyanoethyl,        isobutyl, t-butyl, t-amyl, cyclobutyl, 1-methylcyclobutyl,        cyclopentyl, cyclohexyl, 1-methylcyclohexyl, 1-adamantyl,        isobornyl, vinyl, allyl, cinnamyl, phenyl,        2,4,6-tri-t-butylphenyl, m-nitrophenyl, S-phenyl, 8-quinolinyl,        N-hydroxypiperidinyl, 4-(1,4-dimethylpiperidinyl),        4,5-diphenyl-3-oxazolin-2-one, benzyl, 2,4,6-trimethylbenzyl,        p-methoxybenzyl, 3,5-dimethoxybenzyl, p-decyloxybenzyl,        p-nitrobenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl,        p-bromobenzyl, chlorobenzyl, 2,4-dichloro-benzyl, p-cyanobenzyl,        o-(N,N-dimethylcarboxamidobenzyl)benzyl,        m-chloro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl,        p-(phenylazo)benzyl, p-(p′-methoxyphenylazo)benzyl,        5-benzisoxazolylmethyl, 9-anthrylmethyl, diphenylmethyl,        phenyl(o-nitrophenyl)methyl, di(2-pyridyl)methyl,        1-methyl-1-(4-pyridyl)-ethyl, isonicotinyl, or S-benzyl,        carbamate groups);    -   (b) those which form amide groups (e.g. to provide N-formyl,        N-acetyl, N-chloroacetyl, N-dichloro-acetyl, N-trichloroacetyl,        N-trifluoroacetyl, N-o-nitrophenylacetyl,        N-o-nitrophenoxyacetyl, N-acetoacetyl, N-acetylpyridinium,        N-3-phenylpropionyl, N-3-(p-hydroxyphenyl)-propionyl,        N-3-(o-nitro-phenyl)propionyl,        N-2-methyl-2-(o-nitro-phenoxy)propionyl,        N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,        N-isobutyryl, N-o-nitrocinnamoyl, N-picolinoyl,        N-(N′-acetyl-methionyl), N-(N′-benzoylphenylalanyl), N-benzoyl,        N-p-phenyl-benzoyl, N-p-methoxybenzoyl, N-o-nitrobenzoyl, or        N-o-(benzoyloxy-methyl)benzoyl, amide groups);    -   (c) those which form N-alkyl groups (e.g. N-allyl, N-phenacyl,        N-3-acetoxypropyl, N-(4-nitro-1-cyclohexyl-2-oxo-pyrrolin-3-yl),        N-methoxymethyl, N-chloroethoxymethyl, N-benzyloxymethyl,        N-pivaloyloxymethyl, N-2-tetrahydropyranyl, N-2,4-dinitrophenyl,        N-benzyl, N-3,4-di-methoxybenzyl, N-o-nitrobenzyl,        N-di(p-methoxyphenyl)methyl, N-triphenylmethyl,        N-(p-methoxyphenyl)-diphenylmethyl, N-diphenyl-4-pyridylmethyl,        N-2-picolyl N′-oxide, or N-dibenzosuberyl, groups);    -   (d) those which form N-phosphinyl and N-phosphoryl groups (e.g.        N-diphenylphosphinyl, N-dimethylthiophosphinyl,        N-diphenyl-thiophosphinyl, N-diethyl-phosphoryl,        N-dibenzylphosphoryl, or N-phenylphosphoryl, groups);    -   (e) those which form N-sulfenyl groups (e.g. N-benzenesulfenyl,        N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl,        N-pentachloro-benzenesulfenyl,        N-2-nitro-4-methoxybenzenesulfenyl, or        N-triphenylmethylsulfenyl, groups);    -   (f) those which form N-sulfonyl groups (e.g. N-benzenesulfonyl,        N-p-nitrobenzenesulfonyl, N-p-methoxybenzenesulfonyl,        N-2,4,6-trimethylbenzene-sulfonyl, N-toluenesulfonyl,        N-benzylsulfonyl, N-p-methylbenzyl-sulfonyl,        N-trifluoromethylsulfonyl, or N-phenacylsulfonyl, groups); and    -   (g) that which forms the N-trimethylsilyl group.

Preferred amino protective groups include those which provide thecarbamate, N-alkyl and N-sulfonyl groups mentioned above. Particularprotecting groups thus include tert-butoxycarbonyl (to form atert-butylcarbamate group), benzenesulfonyl, 4-nitrobenzenesulfonyl,3,4-dimethoxybenzyl, o-nitrobenzyl and, especially, benzyl groups.

The skilled person will appreciate that the conversion of theintermediate of formula IV to the compound of formula I is atransformation that is akin to a classical “Hofmann” rearrangement,except that, in the process of the invention, the intermediateisocyanate compound is “trapped” with an alcohol of formula R²OH, asopposed to water. In this respect, agents that may be used to effect therearrangement/oxidation process include combinations of halogenatingagents and bases, such as a combination of a brominating agent and abase. Suitable halogenating agents include any source of “electrophilic”halogen (e.g. N-halosuccinimides and halogens).

Other agents that may be used to effect the above-mentionedrearrangement include Pb(OAc)₄.

Preferred values of R¹ include an amino protective group, or astructural fragment of formula Ia in which:

-   -   R³ represents H, halo, C₁₋₃ alkyl, —OR⁶, —N(H)R⁷ or, together        with R⁴, represents ═O;    -   R⁴ represents H, C₁₋₃ alkyl or, together with R³, represents=O;    -   R⁶ represents H, C₁₋₆ alkyl, -E-phenyl (which phenyl group is        optionally substituted by one or more substituents selected from        cyano, halo, nitro, C₁₋₄ alkyl and C₁₋₄ alkoxy) or -E-Het;    -   R⁷ represents H, C₁₋₆ alkyl, -E-phenyl (which phenyl group is        optionally substituted by one or more substituents selected from        cyano, halo, nitro, C₁₋₄ alkyl and C₁₋₄ alkoxy), —C(O)R^(9a),        —C(O)OR^(9b), —S(O)₂R^(9c), —C(O)N(R^(10a))R^(10b) or —C(NH)NH₂;    -   R^(9a) to R^(9c) independently represent C₁₋₆ alkyl, or R^(9a)        represents H;    -   R^(10a) and R^(10b) independently represent H or C₁₋₄ alkyl;    -   E represents, at each occurrence when used herein, a direct bond        or C₁₋₂ alkylene;    -   A represents -G-, -J-N(R¹¹)— or -J-O— (in which latter two        groups, N(R¹¹)— or O— is attached to the carbon atom bearing R³        and R⁴);    -   B represents -Z-, -Z-N(R¹²)—, -Z-S(O)_(n)— or -Z-O—;    -   G represents C₁₋₄ alkylene;    -   J represents C₂₋₄ alkylene;    -   Z represents a direct bond or C₁₋₃ alkylene;    -   R¹¹ and R¹² independently represent H or C₁₋₄ alkyl;    -   n represents 0 or 2;    -   R⁵ represents phenyl or pyridyl, both of which groups are        optionally substituted by one or more substituents selected from        cyano, halo, nitro, C₁₋₆ alkyl, C₁₋₆ alkoxy, —NH₂,        —C(O)N(R^(14e))R^(14f), —N(R^(14g))C(O)R^(14h) and        —N(R^(14m))S(O)₂R^(13b);    -   R^(13b) represents C₁₋₃ alkyl;    -   R^(14e) to R^(14m) independently represent, at each occurrence        when used herein, H or C₁₋₄ alkyl;    -   Het¹ to Het⁵ are optionally substituted by one or more        substituents selected from ═O, cyano, halo, nitro, C₁₋₄ alkyl,        C₁₋₄ alkoxy, —N(R^(15a))R^(15b), —C(O)R^(15c), or —C(O)OR^(15d);    -   R^(15a) to R^(15d) independently represent H, C₁₋₄ alkyl or        aryl.

Values of R¹ that are more preferred include an amino protective group,or a structural fragment of formula Ia in which:

-   -   R³ represents H, methyl, —OR⁶ or —N(H)R⁷;    -   R⁴ represents H or methyl;    -   R⁶ represents H, C₁₋₂ alkyl or phenyl (which phenyl group is        optionally substituted by one or more substituents selected from        cyano and C₁₋₄ alkoxy);    -   R⁷ represents H, C₁₋₂ alkyl, phenyl (which phenyl group is        optionally substituted by one or more substituents selected from        cyano, halo, nitro, C₁₋₄ alkyl and C₁₋₄ alkoxy), —C(O)R^(9a) or        —C(O)OR^(9b);    -   R^(9a) and R^(9b) independently represent C₁₋₆ alkyl;    -   A represents C₁₋₄ alkylene;    -   B represents -Z-, -Z-N(R¹²)—, -Z-S(O)₂— or -Z-O—;    -   R¹² represents H or methyl;    -   R⁵ represents pyridyl or phenyl, which latter group is        optionally substituted by one to three substituents selected        from cyano, nitro, C₁₋₂ alkoxy, NH₂ and —N(H)S(O)₂CH₃.

Values of R¹ that are more preferred still include an amino protectivegroup, or a structural fragment of formula Ia in which:

-   -   R³ represents H, —OR⁶ or —N(H)R⁷;    -   R represents H or phenyl (optionally substituted by one or more        substituents selected from cyano and C₁₋₂ alkoxy);    -   R⁷ represents H, phenyl (optionally substituted by one or more        cyano groups) or —C(O)O—C₁₋₅ alkyl;    -   A represents C₁₋₃ alkylene;    -   B represents -Z-, -Z-N(H)—, -Z-S(O)₂— or -Z-O—;    -   R⁵ represents phenyl substituted by cyano in the ortho- and/or,        in particular, thepara-position relative to B.

Particularly preferred values of R¹ include an amino protective group,or a structural fragment of formula Ia in which:

-   -   R³represents H or —OH;    -   R⁴ represents H;    -   A represents CH₂;    -   B represents -Z-, -Z-N(H)— or -Z-O—;    -   Z represents a direct bond or C₁₋₂ alkylene;    -   R⁵ represents para-cyanophenyl.

Especially preferred values of R¹ include an amino protective group, orthe following sub-structures

The process of the invention is most preferably carried out to providecompounds of formula I in which R¹ is an amino protective group asdefined above, such as benzyl.

Preferred values of R² include C₁₋₆ alkyl, particularly saturated C₁₋₆alkyl.

More preferred values of R² include saturated C₃₋₅ alkyl, particularlysaturated C₄ alkyl, such as tert-butyl.

Preferred values of R¹⁻⁶ include phenyl, optionally substituted by oneor more (e.g. one to three) substituents (e.g. one substituent) selectedfrom C₁₋₃ alkyl (e.g. methyl), halo and nitro, particularlyunsubstituted phenyl, methylphenyl (such as 4-methylphenyl) ortrimethylphenyl (such as 2,4,6-trimethylphenyl).

The process of the invention is preferably carried out in the presenceof a suitable solvent system. This solvent system should not give riseto stereochemical changes in the reactants or product once formed.

For reaction between compounds of formula II and compounds of formulaIII, the following may be the case.

-   -   (a) Suitable solvents include water and organic solvents.        Preferred solvents include DMF, N-methylpyrrolidinone,        dichloromethane, acetonitrile, DMSO, lower alkyl (e.g. C₁₋₆        alkyl) alcohols (such as ethanol), lower alkyl (e.g. C₁₋₆ alkyl)        esters (e.g. C₁₋₆ alkyl acetates (such as iso-propyl acetate)),        water, aromatic hydrocarbons (such as toluene) or mixtures        thereof. Particularly preferred solvents include iso-propyl        acetate, water, toluene and mixtures thereof.    -   (b) Reaction may be carried out in the presence of a base. In        this respect, suitable bases include tertiary amines such as        tri(C₁₋₆ alkyl)amines (e.g. triethylamine), alkali metal        carbonates and alkali metal hydrogencarbonates and alkali metal        hydroxides. Preferred bases include alkali metal        hydrogencarbonates, such as sodium hydrogencarbonate, and alkali        metal hydroxides, such as sodium hydroxide.    -   (c) Reaction is preferably carried out at, or above, ambient        temperature (e.g. between 10 and 100° C., preferably between 15        and 85° C., and, particularly, between 20 and 75° C.). For        example, where the solvent system that is employed is a mixture        of water and toluene, the reaction may be carried out at between        55 and 75° C. (such as between 65 and 70° C.). Where the solvent        system is toluene (alone), the reaction may be carried out at        between 60 and 70° C.    -   (d) The stoichiometric ratio of the compound of formula II to        the compound of formula III is preferably within the range of        3:2 to 2:3, particularly within the range 5:4 to 8:11 (such as        within the range 11:10 to 5:6), and, especially, within the        range 1:1 to 10:11, such as 1:1.    -   (e) Reaction may, if appropriate be followed by isolation of the        appropriate sulfonic acid salt. We have found advantageously        that where reaction takes place between a compound of formula II        in which R¹ is an amino protective group, such as benzyl, and a        compound of formula III in which R² represents tert-butyl and        R¹⁶ represents 2,4,6-trimethylphenyl, the resultant sulfonic        acid salt may be readily isolated in high purity by way of        simple filtration, particularly when the compounds of formulae        II and III are reacted together by heating in the presence of an        aromatic hydrocarbon, such as toluene as solvent.    -   (f) Irrespective of whether the sulfonic acid salt is isolated,        reaction may be followed by neutralisation of that salt under        appropriate conditions, such as those described hereinafter.

For reaction between compounds of formula II and acrylamide, thefollowing may be the case.

-   -   (A) Suitable solvents include polar solvents such as DMF,        N-methyl-pyrrolidinone, acetonitrile, DMSO, lower alkyl (e.g.        C₁₋₆ alkyl) alcohols (such as ethanol), water, and mixtures        thereof. Preferred solvents include C₁₋₄ alkyl alcohols such as        ethanol.    -   (B) Reaction is preferably carried out in the absence of base,        although a suitable base (such as a tertiary amine (e.g.        triethylamine)) may be employed where the compound of formula II        is provided as an acid addition salt.    -   (C) Reaction is preferably carried out at above ambient        temperature, such as between room and reflux temperature of the        solvent employed (e.g. between 25 and 100° C., preferably        between 45 and 90° C., and, particularly, between 60 and 85°        C.). For example, where the solvent system that is employed is        ethanol, the reaction may be carried out at around reflux        temperature (such as between 65 and 80° C., and, particularly,        between 70 and 80° C.).    -   (D) The stoichiometric ratio of the compound of formula II to        acrylamide is preferably within the range of 3:2 to 2:3,        particularly within the range 5:4 to 8:11 (such as within the        range 11:10 to 5:6), and, especially, within the range 1:1 to        10:11 (such as within the range 1:1 to 20:21.    -   (E) The intermediate compound of formula IV that is formed may        be purified by conventional techniques, such as        recrystallisation. Suitable solvents for such a        recrystallisation procedure include C₃₋₈ alkyl esters (such as        n-propyl acetate, iso-propyl acetate and, particularly, ethyl        acetate).

When the intermediate formed by reaction between compounds of formula IIand acrylamide (the compound of formula IV) is reacted with abrominating agent, base and the alcohol of formula R²—OH, the followingmay be the case.

-   -   (i) Reaction is optionally carried out in the presence of a        suitable solvent system. However, it is preferred that the        alcohol R²—OH is present in excess such that it may act both as        a reagent and as a solvent for the compound of formula IV.    -   (ii) Suitable brominating agents include any source of        ‘electrophilic’ bromine, and thus include bromine and        N-bromoimido compounds. Preferred brominating agents include        N-bromosuccinimide.    -   (iii) Suitable bases include alkali metal hydroxides and        alkoxides. Preferred bases include alkali metal C₁₋₆ alkoxides,        such as potassium C₃₋₅ alkoxides (e.g. potassium tert-butoxide).    -   (iv) Reaction is preferably carried out at above ambient        temperature, such as between room and reflux temperature of the        solvent employed (e.g. between 25 and 100° C., preferably        between 45 and 90° C. and, particularly, between 55 and 80° C.).        For example, when the alcohol is tert-butanol, the reaction may        be carried out at between 55 and 70° C., preferably between 57        and 67° C. and, particularly, between 60 and 65° C.    -   (v) The stoichiometric ratio of the compound of formula IV to        the brominating agent is preferably within the range 1:1 to 1:7,        particularly within the range 2:3 to 1:5 (such as within the        range 1:2 to 1:3) and, especially, within the range 2:5 to 7:20.    -   (vi) The stoichiometric ratio of the compound of formula IV to        the base is preferably within the range 1:1 to 1:20,        particularly within the range 1:2 to 1:10 (such as within the        range 1:3 to 2:15) and, especially, within the range 5:27 to        1:7.

Compounds of formula II may be prepared as described in internationalpatent application WO 01/28992.

For example compounds of formula II may be prepared by dehydrativecyclisation of a corresponding compound of formula V,

or a protected (e.g. N-benzenesulfonyl or N-nitrobenzenesulfonyl (e.g.N-4-nitrobenzenesulfonyl) derivative thereof, wherein R¹ is ashereinbefore defined. This cyclisation may be carried out, for examplein the presence of a suitable dehydrating agent (such as: a strong acid(e.g. sulfuric acid (e.g. concentrated sulfuric acid) or, particularly,methanesulfonic acid (especially anhydrous methanesulfonic acid) and thelike); an acid anhydride such as acetic anhydride ortrifluoromethane-sulfonic anhydride; P₂O₅ in methanesulfonic acid; aphosphorous-based halogenating agent such as P(O)Cl₃, PCl₃ or PCl₅; orthionyl chloride). The cyclisation may also be carried out in thepresence of a suitable organic solvent system, which solvent systemshould not significantly react chemically with, or significantly giverise to stereochemical changes in, the reactant or product once formed,or significantly give rise to other side reactions. Preferred solventsystems include aromatic solvents (e.g. an aromatic hydrocarbon, such astoluene or xylene, or a chlorinated aromatic hydrocarbon, such aschlorobenzene or dichlorobenzene), or dichloroethane, optionally in thepresence of further solvents such as ethanol and/or ethyl acetate. Whenthe dehydrating agent is methanesulfonic acid, preferred solvent systemsinclude toluene. When the dehydrating agent is sulfuric acid, preferredsolvent systems include chlorobenzene or no solvent. The cyclisation maybe carried out at elevated temperature (e.g. up to the refluxtemperature of the relevant solvent system, or higher if a pressurisedsystem is employed). Clearly, appropriate reaction times and reactiontemperatures depend upon the solvent system that is employed, as well asthe reactants that are used and the compound that is to be formed, butthese may be determined routinely by the skilled person.

Compounds of formula II in which R¹ represents H or an amino protectivegroup may alternatively be prepared according to, or by analogy with,known techniques, such as reaction of a compound of formula VI,

wherein R^(1a) represents H or an amino protective group (ashereinbefore defined) and L¹ represents a suitable leaving group (e.g.halo, such as iodo), with ammonia or a protected derivative thereof(e.g. benzylamine), for example under conditions such as those describedin Chem. Ber. 96(11), 2827 (1963).

Compounds of formula II in which R¹ represents a structural fragment offormula Ia may alternatively be prepared by reaction of the compound offormula II in which R¹ represents H(9-oxa-3,7-diazabicyclo[3.3.1]nonane), or a derivative that is protectedat the other nitrogen atom, with a compound of formula VII,

wherein L² represents a leaving group (e.g. mesylate, tosylate,mesitylenesulfonate or halo) and R³, R⁴, R⁵, A and B are as hereinbeforedefined, for example at between −10° C. and reflux temperature (e.g.between room temperature and reflux temperature) in the presence of asuitable base (e.g. triethylamine or an alkali metal hydrogencarbonateor carbonate, such as K₂CO₃) and an appropriate organic solvent (e.g.dichloromethane, acetonitrile, DMSO, chloroform, dimethylformamide, alower (e.g. C₁₋₆) alkyl alcohol (such as ethanol or iso-propanol), ormixtures thereof).

Compounds of formula II in which R¹ represents a structural fragment offormula Ia in which A represents C₂ alkylene and R³ and R⁴ togetherrepresent ═O may alternatively be prepared by reaction of9-oxa-3,7-diazabicyclo[3.3.1]nonane, or a N-protected derivativethereof, with a compound of formula VIII,

wherein R⁵ and B are as hereinbefore defined, for example at roomtemperature in the presence of a suitable organic solvent (e.g.ethanol).

Compounds of formula II in which R¹ represents a structural fragment offormula Ia in which A represents CH₂ and R³ represents —OH or —N(H)R⁷may alternatively be prepared by reaction of9-oxa-3,7-diazabicyclo[3.3.1]-nonane, or a N-protected derivativethereof, with a compound of formula IX,

wherein Y represents O or N(R⁷) and R⁴, R⁵, R⁷ and B are as hereinbeforedefined, for example at elevated temperature (e.g. 60° C. to reflux) inthe presence of a suitable solvent (e.g. a lower (e.g. C₁₋₆) alkylalcohol (e.g. IPA), acetonitrile, water, toluene, a mixture of a lower(e.g. C₁₋₆) alkyl alcohol and water, or a mixture of a lower (e.g. C₁₋₆)alkyl alcohol and toluene).

Other compounds of formula II in which R¹ represents a structuralfragment of formula Ia may alternatively be prepared by knowntechniques, for example according to techniques described in WO01/28992, or by analogy with relevant processes known in the art for theintroduction, and/or chemical conversion, of corresponding side-chainsinto, and/or in (as appropriate), corresponding bispidine compounds, forexample as described in international patent application numbers WO99/31100, WO 00/76997, WO 00/76998, WO 00/76999 and WO 00/77000, thedisclosures in all of which documents are hereby incorporated byreference.

Compounds of formula III may be prepared by reaction of a correspondingcompound of formula X,

wherein R² is as hereinbefore defined, with a compound of formula XI,R¹⁶—S(O)₂-L³   XIwherein L³ represents a leaving group (e.g. halo, such as chloro) andR¹⁶ is as hereinbefore defined, for example at between −20° C. (e.g.−10° C.) and room temperature in the presence of a suitable solvent(e.g. a chlorinated hydrocarbon such as dichloromethane), an appropriatebase (e.g. a tertiary amine such as triethylamine) and a suitablecatalyst (e.g. 4-(dimethyl-amino)pyridine or, preferably, a tertiaryamine acid addition salt such as trimethylamine hydrochloride (seeTetrahedron 55, 2183 (1999)).

Compounds of formula V in which R¹ represents H or an amino protectivegroup may be prepared by reaction of bis(2-oxiranylmethyl)amine (formulaXII),

or a protected (e.g. a N-benzenesulfonyl, or a N-nitrobenzenesulfonyl,such as a N-4-nitrobenzenesulfonyl) derivative thereof, with a compoundof formula XIII,R^(1a)—N²   XIIIwherein R^(1a) is as hereinbefore defined. This reaction may be carriedout at between room temperature and the reflux temperature of anysolvent that is employed (preferably at or around reflux temperature).Suitable solvent systems that may be employed include organic solventsystems, which systems should not significantly react chemically with,or significantly give rise to stereochemical changes in, the reactantsor product once formed, or significantly give rise to other sidereactions. Preferred solvent systems include hydroxylic compounds suchas ethanol, methanol, propan-2-ol, or mixtures thereof (such asindustrial methylated spirit (IMS)), optionally in the presence of anappropriate co-solvent (e.g. an ester, such as ethyl acetate, anaromatic solvent, such as toluene or chlorobenzene, or water). Preferredsolvents for this reaction include primary alcohols such as methanol,propanol and, especially, ethanol, and preferred co-solvents includetoluene and chlorobenzene.

Compounds of formula V in which R¹ represents a structural fragment offormula la may be prepared from the corresponding compound of formula Vin which R¹ represents H (3,7-dihydroxy-1,5-diazacyclooctane) by knowntechniques (e.g. by analogy with the processes described herein inrespect of the preparation of compounds of formula II). In suchreactions, 3,7-dihydroxy-1,5-diazacyclooctane is optionally obtained viadeprotection of a compound of formula V in which R¹ represents an aminoprotective group.

Compounds of formula VI may be prepared by known techniques, for exampleaccording to or by analogy with the procedures described in Chem. Ber.96(11), 2827 (1963) and international patent application WO 01/28992.

Compounds of formula VII may be prepared by standard techniques. Forexample, compounds of formula VII in which:

-   -   (1) B represents -Z-O— may be prepared by coupling a compound of        formula XIV,        R⁵—OH   XIV        -   wherein R⁵ is as hereinbefore defined, to a compound of            formula XV,            L²-Z-C(R³)(R⁴)-A-L²   XV        -   wherein R³, R⁴, A, Z and L² are as hereinbefore defined, and            the two L² groups may be the same or different; or    -   (2) B represents —N(R¹²)-Z- (wherein N(R¹²) is attached to the        carbon atom bearing R³ and R⁴) and R³ and R⁴ together represent        ═O may be prepared by coupling a compound of formula XVI        R⁵-Z-N(H)R¹²   XVI        -   wherein R⁵, R¹² and Z are as hereinbefore defined, to a            compound of formula XVII,            L⁴-C(O)-A-L²   XVII        -   wherein L⁴ represents a suitable leaving group (e.g. —OH or            halo) and A and L² are as hereinbefore defined,    -   in both cases, under conditions which are well known to those        skilled in the art.

Compounds of formula VII in which A represents C₂ alkylene and R³represents —OR⁶, in which R⁶ represents C₁₋₆ alkyl, -E-aryl or -E-Het¹may alternatively be prepared by reaction of a compound of formulaXVIII,R^(6a)—OH   XVIIIwherein R represents C₁₋₆ alkyl, -E-aryl or -E-Het¹, and E and Het¹ areas hereinbefore defined, with a compound of formula XIX,

wherein R¹⁷ represents C₁₋₄ alkyl, and R⁴, R⁵ and B are as hereinbeforedefined, for example at between ambient temperature (e.g. 25° C.) andreflux temperature in the presence of a suitable base (e.g. potassiumcarbonate) and an appropriate organic solvent (e.g. acetonitrile),followed by conversion of the ester functionality to a —CH₂-L² group (inwhich L² is as hereinbefore defined), under conditions that are wellknown to those skilled in the art.

Compounds of formula VII in which A represents C₂₋₆ alkylene may beprepared by reduction of a corresponding compound of formula XX,

wherein A^(a) represents a direct bond or C₁₋₄ alkylene, and R³, R⁴, R⁵and B are as hereinbefore defined, with a suitable borane orborane-Lewis base complex (e.g. borane-dimethyl sulfide) in the presenceof an appropriate solvent (e.g. diethyl ether, THF, or a mixturethereof), followed by oxidation of the resulting borane adduct with asuitable oxidising agent (e.g. sodium perborate) and then conversion ofthe resulting OH group to an L² group under conditions known to thoseskilled in the art.

Compounds of formula VII in which A represents C₁₋₆ alkylene and Brepresents -Z-N(R¹²)— (in which latter case Z is attached to the carbonatom bearing R³ and R⁴) may be prepared by coupling a compound offormula XXI,R⁵-L⁵   XXIwherein L⁵ represents a leaving group such as halo, alkanesulfonate,perfluoroalkanesulfonate or arenesulfonate and R⁵ is as hereinbeforedefined, with a compound of formula XXII,HN(R¹²)-Z-C(R³)(R⁴)-A^(b)-OH   XXIIwherein A^(b) represents C₁₋₆ alkylene, Z, R³, R⁴ and R¹² are ashereinbefore defined, for example at between room and refluxtemperature, optionally in the presence of a suitable solvent and/or anappropriate base, followed by conversion of the OH group to an L² groupunder conditions known to those skilled in the art.

Compounds of formula VII in which B represents -Z-S(O)— or -Z-S(O)₂— maybe prepared by oxidation of corresponding compounds of formula VII inwhich B represents -Z-S—, wherein Z is as hereinbefore defined, in thepresence of an appropriate amount of a suitable oxidising agent (e.g.mCPBA) and an appropriate organic solvent.

Compounds of formula IX may be prepared in accordance with techniquesthat are known to those skilled in the art. For example, compounds offormula IX in which:

-   -   (1) B represents —CH₂O— and Y represents O may be prepared by        reaction of a compound of formula XIV, as hereinbefore defined,        with a compound of formula XXIII        -   wherein R⁴ and L⁵ are as hereinbefore defined, for example            at elevated temperature (e.g. between 60° C. and reflux            temperature) in the presence of a suitable base (e.g.            potassium carbonate or NaOH) and an appropriate organic            solvent (e.g. acetonitrile or toluene/water), or as            otherwise described in the art;    -   (2) R⁴ represents H, B represents a direct bond, C₁₋₄ alkylene,        -Z-N(R¹²)—, -Z-S(O)_(n)— or -Z-O— (in which, in each case, the        group Z represents C₁₋₄ alkylene attached to the carbon atom        bearing R⁴) and Y represents O may be prepared by reduction of a        compound of formula XXIVA or XXIVB,        -   wherein B^(a) represents -Z^(a)-N(R¹²), -Z-^(a)-S(O)_(n)— or            Z^(a)-O— (in which, in each case, the group Z^(a) represents            a direct bond or C₁₋₃ alkylene attached to the carbon atom            bearing R⁴), B^(b) represents a direct bond or C₁₋₄            alkylene, and R⁵, R¹² and n are as hereinbefore defined, for            example at between −15° C. and room temperature in the            presence of a suitable reducing agent (e.g. NaBH₄) and an            appropriate organic solvent (e.g. THF), followed by an            internal displacement reaction in the resultant            intermediate, for example at room temperature in the            presence of a suitable base (e.g. potassium carbonate) and            an appropriate organic solvent (e.g. acetonitrile);    -   (3) B represents a direct bond, C₁₋₄ alkylene, -Z-N(R¹²)—,        -Z-S(O)₂— or -Z-O— (in which, in each case, the group Z        represents C₁₋₄ alkylene attached to the carbon atom bearing R⁴)        and Y represents O may be prepared by oxidation of a compound of        formula XXVA or XXVB,        -   wherein R⁴, R⁵ and B^(b) are as hereinbefore defined, and            B^(a) is as hereinbefore defined except that n represents 2,            in the presence of a suitable oxidising agent (e.g. mCPBA),            for example by refluxing in the presence of a suitable            organic solvent (e.g. dichloromethane); or    -   (4) B represents -Z-O—, in which group Z represents C₁₋₄        alkylene attached to the carbon atom bearing R⁴, and Y        represents —N(R⁷), wherein R⁷ represents —C(O)OR^(9b) or        —S(O)₂R^(9c), may be prepared by cyclisation of a compound of        formula XXVI,        -   wherein R^(7a) represents —C(O)OR^(9b) or —S(O)₂R^(9c),            Z^(b) represents C₁₋₄ alkylene and R⁴, R⁵, R^(9b), R^(9c)            and L⁵ are as hereinbefore defined, for example at between            0° C. and reflux temperature in the presence of a suitable            base (e.g. sodium hydroxide), an appropriate solvent (e.g.            dichloromethane, water, or a mixture thereof) and, if            necessary, a phase transfer catalyst (such as            tetrabutylammonium hydrogensulfate).

Bis(2-oxiranylmethyl)amine (the compound of formula XII) may be preparedby reaction of two or more equivalents of a compound of formula XXVII,

-   -   wherein L³ is as hereinbefore defined, with ammonia, or a        protected (e.g. a benzenesulfonyl, or a nitrobenzenesulfonyl        (e.g. a 4-nitrobenzenesulfonyl)) derivative thereof, for example        at between room and reflux temperature in the presence of a        suitable base (e.g. an alkali metal carbonate such as cesium        carbonate, sodium hydroxide, sodium hydride or lithium        diisopropylamide), an appropriate solvent (e.g. acetonitrile,        N,N-dimethylformamide, THF, toluene, water or mixtures thereof),        and optionally in the presence of a phase transfer catalyst        (e.g. tricaprylylmethylammonium chloride). Preferred bases        include sodium hydroxide and preferred solvents include water.

Compounds of formula XX in which B represents C₁₋₄ alkylene may beprepared by coupling a compound of formula XXVIII,

wherein B^(c) represents C₁₋₄ alkylene, Hal represents chloro, bromo oriodo, and A^(a), R³ and R⁴ are as hereinbefore defined, with a compoundof formula XXI, as hereinbefore defined, for example at between −25° C.and room temperature in the presence of a suitable zinc(II) salt (e.g.anhydrous ZnBr₂), an appropriate catalyst (e.g. Pd(PPh₃)₄ or Ni(PPh₃)₄)and a reaction-inert organic solvent (e.g. THF, toluene or diethylether).

Compounds of formulae VIII, X, XI, XIII, XIV, XV, XVI, XVII, XVIII, XIX,XXI, XXII, XXIII, XXIVA, XXIVB, XXVA, XXVB, XXVI, XXVII and XXVIII, andderivatives thereof, are either commercially available, are known in theliterature or may be obtained by analogy with the processes describedherein, or by conventional synthetic procedures, in accordance withstandard techniques, from readily available starting materials usingappropriate reagents and reaction conditions.

As stated above, the process of the invention is preferably carried outto produce compounds of formula I in which R¹ represents an aminoprotective group, such as benzyl.

A preferred synthesis of compounds of formula I, however, involvessynthesis of compounds of formula I in which R¹ represents a structuralfragment of formula Ia, as hereinbefore defined, which process comprisesthe formation of a compound of formula I in which R¹ represents H or,preferably, an amino protective group (which should subsequently beremoved to form a compound of formula I in which R¹ is H) and subsequentcoupling of the resultant “intermediate” compound of formula I with acompound that provides the structural fragment of formula Ia, forexample as described herein.

Thus, according five further aspects of the invention there is provided:

-   -   (I) a process for the preparation of a compound of formula I in        which R¹ represents H, which process comprises removal of the        amino protective group from a corresponding compound of formula        I in which R¹ represents an amino protective group;    -   (II) a process for the preparation of a compound of formula I in        which R¹ represents H, which process comprises a process as        described hereinbefore for the preparation of a corresponding        compound of formula I in which R¹ represents an amino protective        group followed by removal of the amino protective group;    -   (III) a process for the preparation of a compound of formula I        in which R represents        -   a) a structural fragment of formula Ia,        -   b) a structural fragment of formula Ia, in which A            represents C₂ alkylene and R³ and R⁴ together represent ═O,            or        -   c) a structural fragment of formula Ia, in which A            represents CH₂ and R³ represents —OH or —N(H)R⁷,        -   which process comprises reaction of a corresponding compound            of formula I in which R¹ represents H with        -   1) a compound of formula VII, as hereinbefore defined,        -   2) a compound of formula VIII, as hereinbefore defined, or        -   3) a compound of formula IX, as hereinbefore defined,            respectively;    -   (IV) a process for the preparation of a compound of formula I in        which R¹ represents        -   a) a structural fragment of formula Ia,        -   b) a structural fragment of formula Ia, in which A            represents C₂ alkylene and R³ and R⁴ together represent ═O,            or        -   c) a structural fragment of formula Ia, in which A            represents CH₂ and R³ represents —OH or —N(H)R⁷,        -   which process comprises a process for the preparation of a            corresponding compound of formula I in which R¹ represents            H, as described hereinbefore, followed by reaction of that            compound with        -   1) a compound of formula VII, as hereinbefore defined,        -   2) a compound of formula VIII, as hereinbefore defined, or        -   3) a compound of formula IX, as hereinbefore defined,            respectively; and    -   (V) a process for the preparation of a compound of formula I in        which R¹ represents        -   a) a structural fragment of formula Ia,        -   b) a structural fragment of formula Ia, in which A            represents C₂ alkylene and R³ and R⁴ together represent ═O,            or        -   c) a structural fragment of formula Ia, in which A            represents CH₂ and R³ represents —OH or —N(H)R⁷,        -   which process comprises a process as described hereinbefore            for the preparation of a corresponding compound of formula I            in which R¹ represents an amino protective group, removal of            the amino protective group and subsequent coupling of the            resulting compound of formula I in which R¹ represents H,            with        -   1) a compound of formula VII, as hereinbefore defined,        -   2) a compound of formula VIII, as hereinbefore defined, or        -   3) a compound of formula IX, as hereinbefore defined,            respectively.

In these further aspects of the invention, amino protective groups maybe removed under standard conditions. For example, when the aminoprotective group is benzyl, deprotection may be carried out byhydrogenation at ambient temperature in the presence of a suitablecatalyst (e.g. a supported palladium catalyst, such as Pd/C, e.g. 5%(w/w) Pd/C), an appropriate solvent (e.g. a lower (e.g. C₁₋₆) alkylalcohol, such as ethanol, or an aromatic hydrocarbon, such as toluene,or mixtures thereof) and optionally in the presence of a suitable base(e.g. an alkali metal carbonate or hydrogencarbonate, such as sodiumhydrogencarbonate). Deprotection may also be carried out in the presenceof a suitable acid. Strong acids (e.g. HCl) may be used, though weprefer that the acid is a weaker acid, such as citric acid and the like.

Further, coupling between a compound of formula I in which R¹ representsH and a compound of formula VII, VIII or IX may take place under any ofthe relevant conditions described hereinbefore in respect of respectivepreparations of corresponding compounds of formula II.

In particular, where coupling takes place between a compound of formulaI in which R¹ represents H and a compound of formula VII, then thecoupling is preferably carried out at between 65 and 75° C. (such as at70° C.) in the presence of a C₁₋₆ alkyl alcohol (such as ethanol) assolvent and an alkali metal carbonate (such as K₂CO₃) base.

Further, where coupling takes place between a compound of formula I inwhich R¹ represents H and a compound of formula IX, then the coupling ispreferably carried out at between 50 and 80° C. (such as at between 60and 75° C., such as 70° C. (e.g. 66° C. or 70° C.)) in the presence of aC₁₋₆ alkyl alcohol (such as iso-propanol or ethanol), water and/ortoluene as solvent, and optionally in the presence of a suitable base(e.g. NaOH). Preferred solvents for this reaction include mixtures ofiso-propanol and water, and mixtures of ethanol, water and toluene.

In addition to the further aspects of the invention described above, theskilled person will appreciate that certain compounds of formula I maybe prepared from certain other compounds of formula I or fromstructurally related compounds. For example, compounds of formula I inwhich RI represents certain structural fragments of formula Ia may beprepared in accordance with relevant processes known in the art for theinterconversion of corresponding structural fragments of formula Ia, forexample by analogy with the processes described in international patentapplication numbers WO 99/31100, WO 00/76997, WO 00/76998, WO 00/76999,WO 00/77000 and WO 01/28992.

It will be appreciated by those skilled in the art that, in theprocesses described above, the functional groups of intermediatecompounds may be, or may need to be, protected by protecting groups. Inparticular, it may be desirable to protect the amino group ofbis(2-oxiranylmethyl)amine (the compound of formula XII) with anappropriate protecting group (e.g. benzenesulfonyl, nitrobenzenesulfonyl(such as 4-nitrobenzenesulfonyl)), which should be removed after thecompound of formula II is formed.

In any event, functional groups which it is desirable to protect includehydroxy and amino. Suitable protecting groups for hydroxy includetrialkylsilyl and diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl,tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl andalkylcarbonyl groups (e.g. methyl- and ethylcarbonyl groups). Suitableprotecting groups for amino include the amino protective groupsmentioned hereinbefore, such as benzyl, sulfonyl (e.g. benzenesulfonylor 4-nitrobenzenesulfonyl), tert-butyloxycarbonyl,9-fluorenylmethoxycarbonyl or benzyloxycarbonyl.

The protection and deprotection of functional groups may take placebefore or after any of the reaction steps described hereinbefore.

Protecting groups may be removed in accordance with techniques which arewell known to those skilled in the art and as described hereinafter.

The use of protecting groups is fully described in “Protective Groups inOrganic Chemistry”, edited by J. W. F. McOmie, Plenum Press (1973), and“Protective Groups in Organic Synthesis”, 3^(rd) edition, T. W. Greene &P. G. M. Wutz, Wiley-Interscience (1999).

The process of the invention possesses the surprising advantage thatcompounds of formula I may be prepared conveniently from solid (asopposed to, for example, oily or semi-solid) precursors, whichprecursors may be purified using simple procedures (e.g.recrystallisation).

Further, the process of the invention may have the advantage thatcompounds of formula I may be prepared in higher yields, by way of fewersteps, in less time, more conveniently, and at a lower cost, than whenprepared according to the process described in international patentapplication WO 01/28992.

The invention is illustrated, but in no way limited, by the followingexamples.

EXAMPLES

General Experimental Procedures

Mass spectra were recorded on one of the following instruments: a WatersZMD single quad with electrospray (S/N mc350); a Perkin-Elmer SciX API150ex spectrometer; a VG Quattro II triple quadrupole; a VG Platform IIsingle quadrupole; or a Micromass Platform LCZ single quadrupole massspectrometer (the latter three instruments were equipped with apneumatically assisted electrospray interface (LC-MS)). ¹H NMR and ¹³CNMR measurements were performed on Varian 300, 400 and 500spectrometers, operating at ¹H frequencies of 300, 400 and 500 MHzrespectively, and at ¹³C frequencies of 75.5, 100.6 and 125.7 MHzrespectively.

Rotamers may or may not be denoted in spectra depending upon ease ofinterpretation of spectra. Unless otherwise stated, chemical shifts aregiven in ppm with the solvent as internal standard.

Preparation A 2-(tert-Butyloxycarbonylamino)ethyl tosylate

A solution of p-toluenesulfonyl chloride (28.40 g, 148 mmol) indichloromethane (100 mL) was added dropwise over 30 minutes at 0° C. toa mixture of tert-butyl N-(2-hydroxyethyl)carbamate (20 g, 120 mmol),triethylamine (18.80 g, 186 mmol) and trimethylammonium chloride (1.18g, 12.4 mmol) in dichloromethane (120 mL). The mixture was stirred at 0°C. for 1 hour then filtered, washing with dichloromethane (100 mL). Thefiltrate was washed with 10% citric acid (3×100 mL) and brine (100 mL).The organic layer was dried with magnesium sulfate and then filtered.The filtrate was concentrated under reduced pressure to give an oil. Theoil was dissolved in ethyl acetate (40 mL) and then iso-hexane (160 mL)was added slowly. The resultant slurry was stirred at room temperaturefor 17 hours and then filtered. The collected solid was washed withiso-hexane (240 mL) to yield the title compound as a colourless powder(25 g, 64%).

m.p. 64-66° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.40 (9H, s), 2.45 (3H, s), 3.38 (2H, q), 4.07(2H, t), 4.83 (1H, bs) 7.34 (2H, d), 7.87 (2H, d).

MS: m/z=216 (MH⁺(316)-Boc).

Preparation B 3-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane (i)NN-Bis(2-oxiranylmethyl)benzenesulfonamide

Water (2.5 L, 10 vol.) followed by epichlorohydrin (500 mL, 4 eq.) wereadded to benzenesulfonamide (250 g, 1 eq.). The reactants were heated to40° C. Aqueous sodium hydroxide (130 g in 275 mL of water) was addedsuch that the temperature of the reaction remained between 40° C. and43° C. This took approximately 2 hours. (The rate of sodium hydroxideaddition needs to be slower at the start of the addition than at the endin order to keep within the temperature range stated.) After theaddition of sodium hydroxide was complete, the reaction was stirred at40° C. for 2 hours, then at ambient temperature overnight. The excessepichlorohydrin was removed as a water azeotrope by vacuum distillation(ca. 4 kPa (40 mbar), internal temp 30° C.), until no moreepichlorohydrin distilled. Dichloromethane (1L) was added and themixture stirred rapidly for 15 minutes. The phases were allowed toseparate (this took 10 minutes although totally clear phases areobtained after standing overnight). The phases were separated and thedichloromethane solution used in the subsequent step below.

¹H NMR (400 MHz, CDCl₃): δ 2.55-2.65 (2H, m), 2.79 (2H, t, J 4.4),3.10-3.22 (4H, m), 3.58-3.73 (2H, m), 7.50-7.56 (2H, m), 7.58-7.63 (1H,m), 7.83-7.87 (2H, m).

(ii) 5-Benzyl-3,7-dihydroxy-1-phenylsulfonyl-1,5-diazacyclooctane

IMS (2.5 L, 10 vol) was added to the dichloromethane solution from step(i) above. The solution was distilled until the internal temperaturereached 70° C. Approximately 1250 mL of solvent was collected. More IMS(2.5 L, 10 vol) was added followed by benzylamine (120 mL, 0.7 eq.) inone portion (no exotherm seen), and the reaction was heated at refluxfor 6 hours (no change from 2 hour sampling point). More benzylamine wasadded (15 mL) and the solution was heated for a further 2 hours. The IMSwas distilled off (ca. 3.25 L) and toluene was added (2.5 L). Moresolvent was distilled (ca. 2.4 L) and then further toluene added (1 L).The head temperature was now 110° C. A further 250 mL of solvent wascollected at 110° C. Theoretically, this left the product in ca. 2.4 Lof toluene at 110° C.

This solution was used in the next step.

¹H NMR (400 MHz, CDCl₃): δ 7.83-7.80 (4H, m, ArH), 7.63-7.51 (6H, m,ArH), 7.30-7.21 (10H, ArH), 3.89-3.80 (4H, m, CH(a)+CH(b)), 3.73 (2H, s,CH₂Ph(a)), 3.70 (2H, s, CH₂Ph(b)), 3.59 (2H, dd, CHHNSO₂Ar(a)), 3.54(2H, dd, CHHNSO₂Ar(b)), 3.40 (2H, dd, CHHNSO₂Ar(b)), 3.23 (2H, dd,CHHNSO₂Ar(a)), 3.09-2.97 (4H, m, CHHNBn(a)+CHHNBn(b)), 2.83 (2H, dd,CHHNBn(b)), 2.71 (2H, dd, CHHNBn(a))

(Data taken from purified material comprising a 1:1 mixture of trans-(a), and cis-diol (b))

(iii) 3-Benzyl-7-(phenylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane

The toluene solution from the previous step (ii) above was cooled to 50°C. Anhydrous methanesulfonic acid (0.2 L) was added. This caused atemperature rise from 50° C. to 64° C. After 10 minutes, methanesulfonicacid was added (1 L) and the reaction heated to 110° C. for 5 hours.Toluene was then distilled from the reaction; 1.23 L was collected.(Note that the internal temperature should not be allowed higher than110° C. at any stage otherwise the yield will be decreased.) Thereaction was then cooled to 50° C. and a vacuum applied to remove therest of the toluene. Heating to 110° C. and 65 kPa (650 mbar) allowed afurther 0.53 L to be removed. (If the toluene can be removed at a lowertemperature and pressure then that is beneficial.) The reaction was thenleft to cool to 30° C. and deionised water (250 mL) was added. Thiscaused the temperature to rise from 30° C. to 45° C. More water (2.15 L)was added over a total time of 30 minutes such that the temperature wasless than 54° C. The solution was cooled to 30° C. and thendichloromethane (2 L) was added. With external cooling and rapidstirring, the reaction mixture was basified by adding aqueous sodiumhydroxide (10 M, 2 L) at a rate that kept the internal temperature below38° C. This took 80 minutes. The stirring was stopped and the phasesseparated in 3 minutes. The layers were partitioned. IMS (2 L) was addedto the dichloromethane solution and distillation started. Solvent (2.44L) was collected until the head temperature reached 70° C.Theoretically, this left the product in 1.56 L of IMS. The solution wasthen allowed to cool to ambient temperature overnight with slowstirring. The solid product that precipitated was filtered and washedwith IMS (0.5 L) to give a fawn-coloured product that, on drying at 50°C., in vacuum, gave 50.8 g (8.9% over 3 steps).

20.0 g of this product was dissolved in acetonitrile (100 mL) at refluxto give a pale yellow solution. After cooling to ambient temperature,the crystals that formed were collected by filtration and washed withacetonitrile (100 mL). The product was dried in vacuo at 40° C. for 1hour to give 17.5 g (87%) of sub-title compound.

¹H NMR (400 MHz, CDCl₃): δ 7.18-7.23 (1OH, m), 3.86-3.84 (2H, m), 3.67(2H, d), 3.46 (2H, s), 2.91 (2H, d), 2.85 (2H, dd), 2.56 (2H, dd)

(iv) 3-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane dihydrochloride

Concentrated hydrobromic acid (1.2 L, 3 rel. vol.) was added to solid3-benzyl-7-(phenylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane (400 g,see step (iii) above) and the mixture was heated to reflux under anitrogen atmosphere. The solid dissolved in the acid at 95° C. Afterheating the reaction for 8 hours, HPLC analysis showed that the reactionwas complete. The contents were cooled to room temperature. Toluene (1.2L, 3 rel. vol.) was added and the mixture stirred vigorously for 15minutes. Stirring was stopped and the phases were partitioned. Thetoluene phase was discarded along with a small amount of interfacialmaterial. The acidic phase was returned to the original reaction vesseland sodium hydroxide (10 M, 1.4 L, 3.5 rel. vol.) was added in oneportion. The internal temperature rose from 30° C. to 80° C. The pH waschecked to ensure it was >14. Toluene (1.6 L, 4 rel. vol.) was added andthe temperature fell from 80° C. to 60° C. After vigorous stirring for30 minutes, the phases were partitioned. The aqueous layer was discardedalong with a small amount of interfacial material. The toluene phase wasreturned to the original reaction vessel, and 2-propanol (4 L, 10 rel.vol.) was added. The temperature was adjusted to between 40° C. and 45°C. Concentrated hydrochloric acid (200 mL) was added over 45 minutessuch that the temperature remained at between 40° C. and 45° C. A whiteprecipitate formed. The mixture was stirred for 30 minutes and thencooled to 7° C. The product was collected by filtration, washed with2-propanol (0.8 L, 2 rel vol.), dried by suction and then further driedin a vacuum oven at 40° C. Yield=297 g (91%).

¹H NMR (CD₃OD+4 drops D₂O): δ 2.70 (br d, 2H), 3.09 (d, 2H), 3.47 (br s,4H), 3.60 (s, 2H), 4.12 (br s, 2H), 7.30-7.45 (m, 5H).

API MS: m/z=219 [C₁₃H₁₈N₂O+H]⁺.

(v) 3-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane

All volumes and equivalents are measured with respect to the amount of3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane dihydrochloride (see step(iv) above) used. Toluene (420 mL, 7 vols) and aqueous sodium hydroxidesolution (2M, 420 mL, 7 vols, 4.0 eq) were added to3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane dihydrochloride (60.07 g,206.03 mmole, 1.0 eq., see step (iv) above). The mixture was stirredunder nitrogen, heated to 60° C. and held at this temperature for 30minutes by which time two clear layers had formed. The lower, aqueouslayer was removed, and the toluene solution of title compound (freebase) was azeodried at atmospheric pressure (total volume of solventremoved=430 mL; total volume of toluene added=430 mL), then concentratedto a volume of 240 mL (4 vols). Karl Fischer analysis at this stageshowed 0.06% water in the solution. The dried solution of title compound(theoretically 44.98 g, 206.03 mmole, 1:0 eq) was used as such in asubsequent step.

Preparation C 3-(4-Cyanoanilino)propyl 4-methylbenzenesulfonate

Alternative I

(i) 4-[(3-Hydroxypropyl)amino]benzonitrile

A mixture of 4-fluorobenzonitrile (12.0 g, 99.1 mmol) and3-amino-1-propanol (59.6 g, 793 mmol) was stirred at 80° C. under aninert atmosphere for 3 hours before water (150 mL) was added. Themixture was allowed to cool to rt, and was then extracted with diethylether. The organic layer was separated, dried (Na₂SO₄), filtered andconcentrated in vacuo to yield 17 g (97%) of the sub-title compound asan oil that crystallised upon standing.

(ii) 3-(4-Cyanoanilino)propyl 4-methylbenzenesulfonate

A cooled (0° C.) solution of 4-[(3-hydroxypropyl)amino]benzonitrile(from step (i) above; 17 g, 96.5 mmol) in dry MeCN (195 mL) was treatedwith triethylamine (9.8 g, 96.5 mmol) and then p-toluenesulfonylchloride (20.2 g, 106 mmol). The mixture was stirred at 0° C. for 90minutes before being concentrated in vacuo. Water (200 mL) was added tothe residue, and the aqueous solution was extracted with DCM. Theorganic phase was dried (Na₂SO₄), filtered and concentrated in vacuo.The resulting residue was purified by crystallisation from iso-propanolto yield 24.6 g (77%) of the title compound.

Alternative II (a) 4-[(3-Hydroxypropyl)amino]benzonitrile

4-Fluorobenzonitrile (24.6 g, 0.203 mol, Aldrich 99%) was added to3-amino-1-propanol (122.0 g, 1.625 mol, 8 equiv., Aldrich 99%) and themixture heated to 80° C. for 5 hours, under nitrogen. The solution wasallowed to cool to 22° C. and water (300 mL) was added. The cloudysolution was extracted twice with methylene chloride (300 mL and 200 mL)and the combined methylene chloride extracts were washed with water (300mL) (Note 1).

(b) 3-(4-Cyanoanilino)propyl 4-methylbenzenesulfonate

The solution of the crude 4-[(3-hydroxypropyl)amino]benzonitrile (seestep (a) above) was concentrated to a volume of 300 mL by distillationand a further 200 mL methylene chloride added and redistilled to 300 mL(Note 2). Triethylamine (20.55 g, 0.203 mol), followed by4-(N,N-dimethyl-amino)pyridine (248 mg, 2.0 mmol) was added and thesolution was cooled to 0° C. A solution of tosyl chloride (38.70 g,0.203 mol) in methylene chloride (150 mL) added over ca. 30 minutes withcooling and good agitation, allowing the temperature to rise to 5° C.The reaction was stirred for 23 hours in the range 3 to 5° C. (Note 3)under nitrogen. Water (300 mL) was added and the layers vigorouslyagitated for 15 min. The organic solution was concentrated bydistillation at 35 to 40° C. to a volume of ca. 60 to 70 mL.iso-Propanol (100 mL) was added over 5 minutes (Note 4). Distillationwas continued using house vacuum to remove the last of the methylenechloride (Note 5). The crystal slurry was cooled to 0 to 5° C. over ca.1 hour with slow agitation and held for one hour at 0-5° C. The crystalswere filtered on a medium sinter and the compacted damp filter cakecarefully washed with cold (0° C.) iso-propanol (80 mL). The filter cakewas dried under vacuum and a stream of nitrogen overnight. Yield: 52.6g, 78.4 mole %; HPLC: 99.64 area %.

Notes:

-   -   1. GC analysis of organic layer gave ˜1.0 area % aminopropanol        remaining.    -   2. Solution water by KF 0.07%    -   3. After 5 hours, triethylamine hydrochloride precipitation        occurred. TLC showed very little if any further conversion of        residual cyano alcohol at 20-23 hours.    -   4. At this stage, some granular precipitation of product        occurred prior to addition of iso-propanol. Crystallization        occurred rapidly upon addition of iso-propanol.    -   5. A further ˜30 mL was removed—distillate checked by GC for        absence of methylene chloride.    -   6. Microanalysis: found (theory): %C: 61.60 (61.67); % H: 5.41        (5.49); % N: 8.44 (8.47); %S: 9.71(9.70).

Preparation D 4-[(2S)-Oxiranylmethoxy]benzonitrile

Potassium carbonate (414 g) and (R)-(−)-epichlorohydrin (800 mL) wereadded to a stirred solution of p-cyanophenol (238 g) in 2.0 L MeCN andthe reaction mixture was refluxed under an inert atmosphere for 2 h. Thehot solution was filtered and the filtrate concentrated, giving a clearoil which was crystallised from di-iso-propyl ether giving the productin 90% yield.

Preparation E 2-(tert-Butyloxycarbonylamino)ethyl2,4,6-trimethylbenzenesulfonate

Triethylamine (65 mL, 465.3 mmole, 1.5 eq) was added in one portion to asolution of tert-butyl N-(2-hydroxyethyl)carbamate (50.11 g, 310.2mmole, 1.0 eq.) in dichloromethane (250 mL, 5 vols). The solution wascooled to −10° C. and trimethylamine hydrochloride (14.84 g, 155.1mmole, 0.5 eq.) was added in one portion. The resultant mixture wascooled further to −15° C., stirred for 5 minutes, then treated with asolution of mesitylenesulfonyl chloride (74.74 g, 341.2 mmole, 1.1 eq)in dichloromethane (250 mL, 5 vols), over 28 minutes such that theinternal temperature remained below −10° C. Once the addition wascomplete a precipitate had formed and the mixture was stirred at −10° C.for a further 30 minutes. Water (400 mL, 8 vols) was added and all ofthe precipitate dissolved. The mixture was stirred rapidly for 5minutes, and then the two layers were separated. A solvent swap fromdichloromethane to IPA was carried out by distillation at reducedpressure. Solvent was removed (450 mL) and replaced with IPA (450 mL)(initial pressure was 450 mbar, b.p. 24° C.; final pressure was 110mbar, b.p. 36 ° C.). At the end of the distillation, solvent (150 mL)was removed to bring the volume down to 350 mL (7 vols with respect tothe amount of tert-butyl N-(2-hydroxyethyl)carbamate used). The solutionwas cooled to 25° C., then water (175 mL) was added slowly withstirring, causing the solution gradually to turn cloudy. No solid hadprecipitated at this stage. More water (125 mL) was added, and a solidprecipitate started to form after about 75 mL had been added. Theinternal temperature rose from 25° C. to 31° C. The mixture was stirredslowly and cooled to 7° C. The solid was collected by filtration, washedwith IPA:water (1:1, 150 mL) and dried in vacuo at 40° C. for 21 hoursto give the title compound as a white crystalline solid (92.54 g, 87%).

m.p. 73.5° C.

¹H-NMR (300MHz, CDCl₃) δ 1.42 (9H, s), 2.31 (3H, s), 2.62 (6H, s) 3.40(2H, q), 4.01 (2H, t), 4.83 (1H, bs), 6.98 (2H, s)

Example 1[2-(7-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamic acidtert-butyl ester via nucleophilic substitution reaction Alternative I[2-(7-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamic acidtert-butyl ester

A solution of 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonanedihydro-chloride (see Preparation B(iv) above; 10 g, 34 mmol) in water(25 mL) was added slowly to a solution of sodium bicarbonate (10 g, 119mmol) in water 10 mL). More water (5 mL) was added and the mixture wasstirred at room temperature for 10 minutes. A solution of2-(tert-butyloxycarbonylamino)-ethyl tosylate (see Preparation A above;11.92 g, 37 mmol) in toluene (40 mL) was added. This mixture was thenheated at 65-70° C. for 7 hours before stirring at room temperatureovernight. The reaction was reheated to 50° C. and the phases wereseparated. The aqueous layer was extracted with toluene (40 mL) at 50°C. The combined organic layers were washed with saturated sodiumbicarbonate (25 mL). The solvents were evaporated under reduced pressureto yield a mixture of oil and solid (13 g, >100%). Ethyl acetate (50 mL)and citric acid (10%, 25 mL) were added to a portion of the oily solid(5 g, 138 mmol). The aqueous layer was separated and the organic layerwashed again with citric acid (10%, 20 mL). The aqueous layers werecombined and treated with solid sodium bicarbonate until neutral. Theaqueous phase was extracted with ethyl acetate (2×50 mL), dried overmagnesium sulfate and filtered. The filtrate was evaporated to drynessunder reduced pressure to give the title compound as a colourlesssemi-solid, which solidified fully when stored in the refrigerator (4.68g, 93%).

m.p. 58-60° C.

¹H-NMR (300MHz, CDCl₃) δ 1.46 (9H, s), 2.38-2.57 (4H, m), 2.6-2.68 (2H,m) 2.75-2.85 (4H, m), 3.22 (2H, q), 3.26 (2H, s), 3.83 (2H, bs), 6.17(1H, bs) 7.2-7.4 (5H, m).

MS: m/z =362 (MH⁺).

Alternative II[2-(7-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamic acidtert-butyl ester, 2,4,6-trimethylbenzenesulfonic acid salt

A warm (28° C.) solution of 2-(tert-butyloxycarbonylamino)ethyl2,4,6-trimethylbenzenesulfonate (70.93 g, 206.03 mmole, 1.0 eq, seePreparation E above) in toluene (240 mL, 4 vols) was added to a solutionof 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane (44.98 g, 206.03 mmole,1.0 eq.) in toluene (240 mL, 4 vols) (see Preparation B above). Theresultant solution was stirred rapidly under nitrogen, with heating at68° C. for 8 hours. The reaction was left to stir at ambient temperaturefor 84 hours. A thick, white solid precipitate had formed in a paleyellow solution. The mixture was cooled to +9° C., and title compoundwas collected by filtration. The reaction vessel was washed with toluene(100 mL) and added to the filter. The filter cake was washed withtoluene (150 mL). The white solid product was suction dried for 15minutes, then dried to constant weight in vacuo at 40° C. for 23 hours.The yield of title compound obtained was 79.61 g, 141.7 mmole, 69%. Thecombined filtrate and washings (670 mL) were washed with aqueous sodiumhydroxide solution (2M, 200 mL, 3.3 vols). The mixture was heated to 60°C., and held at this temperature for 20 minutes with rapid stirring. Thetwo layers were then separated. The toluene solution was concentrated to200 mL by vacuum distillation (bp 50-54° C. at 650-700 mbar; bp 46° C.at 120 mbar at the end). As the distillation progressed, the solutionbecame cloudy due to the formation of title compound. It was assumedthat 20% of the original amount of3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane remained in the filtrate,and so extra 2-(tert-butyloxycarbonylamino)ethyl2,4,6-trimethylbenzenesulfonate (14.20 g, 41.21 mmole, 0.2 eq) was addedin one portion (charged as a solid rather than as a solution intoluene). The cloudy solution was heated at 67° C. for 8 hours withrapid stirring, and then left to stir at ambient temperature for 11hours. The mixture was cooled to +8° C., and title compound wascollected by filtration. The reaction vessel was washed with moretoluene (2×30 mL), and added to the filter. The white solid product wassuction dried for 15 minutes, then dried to constant weight in vacuo at40° C. for 7 hours. The yield of title compound was 23.25 g, 41.39mmole, 20%. The combined yield of title compound (a white solid) was102.86 g, 183.11 mmole, 89%. m.p. 190-190.5° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.43 (9H, s), 2.17 (3H, s), 2.51 (6H, s),2.73-2.80 (2H, m), 2.90-2.94 (4H, m), 3.14-3.22 (4H, m), 3.37 (2H, bm),3.89 (2H, bs), 4.13 (2H, bs), 6.74 (2H, s), 7.12 (1H, bt), 7.42-7.46(5H, m)

Example 2[2-(7-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamic acidtert-butyl ester via Michael addition of acrylamide (i)3-(7-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propionamide

Triethylamine (3.60 g, 35.7 mmol) was added slowly to a solution of3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane dihydrochloride (seePreparation B(iv) above; 5 g, 17 mmol) in ethanol (50 mL). Acrylamide(1.34 g, 18 mmol) was added to this mixture, which was then heated atreflux for 7 hours. The reaction mixture was then concentrated underreduced pressure. Water (50 mL) and sodium hydroxide (1 M, 150 mL) wereadded to the residue and the mixture extracted with ethyl acetate (2×200mL). The combined organic extracts were dried over magnesium sulfate,filtered and concentrated under reduced pressure to give a colourlesssolid. This was recrystallised from ethyl acetate (50 mL) to give thesub-title compound (3.80 g, 76%).

m.p. 157-159° C.

¹H-NMR (300 MHz, CDCl₃) δ 2.39 (2H, t), 2.42-2.61 (6H, m), 2.82-2.95(4H, m), 3.39 (2H, s), 3.91 (2H, bs), 5.07 (1H, bs), 7.18-7.21 (2H, m),7.25-7.39 (3H, m), 9.5 (1H, bs).

MS: m/z =290 (MH⁺).

(ii) [2-(7-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamicacid tert-butyl ester

N-Bromosuccinimide (6.0 g, 33 mmol) was added in portions over 1 minuteto a solution of3-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-propionamide (seestep (i) above; 5 g, 12 mmol) in potassium tert-butoxide in tert-butanol(1 M, 81 mL) and tert-butanol (20 mL). The mixture was then heated at60-65° C. for 30 minutes. The reaction was allowed to come to roomtemperature and then water (100 mL) was added. The mixture was extractedwith ethyl acetate (2×50 mL). The combined organic extracts were washedwith brine (50 mL), dried over magnesium sulfate, filtered (washing thefilter cake with ethyl acetate (50 mL)) and then the filtrateconcentrated under reduced pressure to give the title compound as abrown oil (6.5 g, >100%).

¹H-NMR (300 MHz, CDCl₃) δ 1.46 (9H, s), 2.4-2.58 (4H, m), 2.58-2.7 (2H,m) 2.75-2.91 (4H, m), 3.22 (2H, q), 3.28 (2H, s), 3.83 (2H, bs), 6.19(1H, bs) 7.2-7.42 (5H, m).

MS: m/z=316 (MH⁺).

Example 3 [2-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamic acidtert-butyl ester Alternative I

Sodium bicarbonate (0.058 g, 0.069 mmol) and 5% Pd/C (0.250 g, JohnsonMatthey Type 440 paste) were added to a solution of[2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamic acidtert-butyl ester (see Example 1 (Alternative I) above; 1 g, 2.77 mmol)in ethanol (10 mL). The mixture was then hydrogenated at 500 kPa (5 bar)for 18 hours. The reaction mixture was filtered through Celite® and thenwashed with ethanol (20 mL). The solution was concentrated under reducedpressure to give an oil. This was dissolved in dichloromethane (20 mL)and washed with sodium hydroxide (1 M, 10 mL). The organic phase wasseparated, dried over magnesium sulfate and then filtered. The filtratewas concentrated under reduced pressure to give the title compound as ayellow solid (0.67 g, 87%).

m.p. 91-93° C.

¹H-NMR (300MHz, CDCl₃) δ 1.46 (9H, s), 2.25 (2H, t), 2.58-2.65 (2H, m)2.95-3.06 (4H, m), 3.2-3.38 (4H, m), 3.64 (2H, bs), 4.65 (1H, bs).

MS: m/z =272 (MH⁺).

Alternative II

[2-(7-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamic acidtert-butyl ester 2,4,6-trimethylbenzenesulfonic acid salt (320 g, 1.0mol eq, 1.0 rel vol/wt, see Example 1 (Alternative II) above), toluene(640 mL, 2.0 vol) and aqueous sodium hydroxide (1M, 1.6 L, 5.0 vol) werestirred together for 15 minutes and the layers were then separated. Theorganic layer, containing[2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-ethyl]carbamic acidtert-butyl ester, was diluted with ethanol (690 mL, 2.16 vol) and water(130 mL, 0.4 vol). Citric acid (32.83g, 0.3 mol eq) and 5% Pd/C (20.8 g,0.065 wt eq of 61% water wet catalyst, Johnson Matthey type 440L) wereadded. The combined mixture was then hydrogenated under 4 bar ofhydrogen pressure for 24 hours. The reaction was monitored by TLC, usinga silica plate with mobile phase X:DCM (1:1 v/v; X ischloroform:methanol:concentrated ammonia 80:18:2 v/v). Visualisation wasby UV light (254 nm) and by staining with aqueous potassiumpermanganate. This showed the complete disappearance of startingmaterial and the appearance of the title compound. The reaction mixturewas filtered through kieselguhr and was washed with ethanol (590 mL,1.84 vol). The resulting solution of title compound (assumed 154.85 g,100%) was used directly in a subsequent reaction.

Alternative III

[2-(7-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-ethyl]-carbamic acidtert-butyl ester 2,4,6-trimethylbenzenesulfonic acid salt (50 g, 1.0 moleq., 1.0 rel vol/wt, see Example 1 (Alternative II) above), toluene (100mL, 2.0 vol) and aqueous sodium hydroxide (1M, 100 L, 2.0 vol) werestirred together for 20 minutes, then at 30° C. for 10 minutes, and thelayers were then separated. The organic layer, containing[2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamic acidtert-butyl ester, was diluted with ethanol (100 mL, 2.0 vol.). To thiswas added a solution of citric acid (5.14 g, 0.3 mol eq) in water (5 mL,0.1 vol), followed by 5% Pd/C (1.50 g, 0.03 wt eq of 61% water wetcatalyst, Johnson Matthey type 440L). The combined mixture was thenhydrogenated under 4 bar of hydrogen pressure for 24 hours. The reactionwas monitored by TLC, using a silica plate with mobile phase X:DCM 1:1v/v, (X is chloroform: methanol:concentrated ammonia 80 :18:2 v/v).Visualisation was by UV light (254 m-n) and by staining with aqueouspotassium permanganate. This showed the complete disappearance ofstarting material and the appearance of the title compound. The reactionmixture was basified with aqueous sodium hydroxide (10M, 8 mL, 0.9 moleq), then filtered through kieselguhr. The filter-cake was washed withethanol (100 mL, 2.0 vol). The resulting solution of title compound(assumed 24.15 g, 100%) was used directly in a subsequent reaction.

Example 4(2-{7-[3-(4-Cyanoanilino)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-ethyl)carbamicacid tert-butyl ester Alternative 1

3-(4-Cyanoanilino)propyl-4-methylbenzenesulfonate (see Preparation Cabove; 0.30 g, 0.92 mmol) and potassium carbonate (0.2 g, 1.38 mmol)were added to a solution of[2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamic acid tert-butylester (see Example 3 (Alternative I) above; 0.250 g, 0.92 mmol) inethanol (5 mL). The reaction mixture was heated to 70° C. for 10 hoursbefore concentrating the mixture under reduced pressure. The residue waspartitioned between ethyl acetate (20 mL) and sodium hydroxide (1 M, 10mL). The aqueous phase was re-extracted with ethyl acetate (20 mL). Thecombined organic phases were concentrated under reduced pressure to givea yellow solid (0.290 g). The solid was dissolved in ethyl acetate (10mL) and this solution washed with a solution of citric acid (0.250 g) inwater (10 mL). The aqueous phase was separated, basified with sodiumhydroxide (1 M, 10 mL) and extracted with ethyl acetate (2×10 mL). Allorganic phases were combined, dried over magnesium sulfate and thenfiltered (washing filtered solids with ethyl acetate (10 ML)). Thefiltrate was concentrated under reduced pressure to give a yellow solid(0.160 g). This was slurried in ethyl acetate (0.2 mL) and then filteredto give title compound (0.050 g, 12%).

m.p 113-115° C.

¹H-NMR (400 MHz, DMSO-D₆) δ 1.32 (9H, s), 1.7 (2H, qt), 2.20 (2H, t),2.22-2.3 (4H, m), 2.38-3.1 (2H, m) 2.8-2.85 (4H, m), 3.05 (2H, q), 3.19(2H, q), 3.79 (2H, bs), 6.47 (1H, t), 6.66 (2H, d), 6.69 (1H, t), 7.41(2H, d).

MS: m/z=430 (MH⁺).

Alternative 2 (a) 3-(4-Cyanoanilino)propyl benzenesulfonate

To the solution of 4-[(3-hydroxypropyl)amino]benzonitrile (seePreparation C above (first steps of both Alternatives); assumed 43.65 g,247.7 mmol, 1.0 eq) in dichloromethane (360 mL total solution volume)was added, sequentially, triethylamine (52 mL, 37.60 g, 371.55 mmol, 1.5eq) and trimethylamine hydrochloride (11.89 g, 123.85 mmol, 0.5 eq) inone portion. The yellow solution was cooled to −20° C. (using a coldplate), and treated with a solution of benzenesulfonyl chloride (32 mL,43.74 g, 247.7 mmol, 1.0 eq) in dichloromethane (220 mL, 5 vols withrespect to the cyanoalcohol) via a pressure equalising dropping funnel.The solution was added portionwise such that the internal temperaturedid not exceed −14° C. The addition took 25 minutes to complete. Themixture was then stirred for 35 minutes at between −15 and −10° C. Water(365 mL) was added and the temperature rose to 10° C. The mixture wascooled back to 0° C. and stirred vigorously for 15 minutes. The organiclayer (volume 570 mL) was collected and distilled at atmosphericpressure to remove DCM (450 mL, pot temperature 40-42° C., still-headtemperature 38-39° C.). Ethanol (250 mL) was added, and the solution wasallowed to cool to below 30° C. before turning on the vacuum. Moresolvent was removed (40 mL was collected, pressure 5.2 kPa (52 mbar),pot and still-head temperatures were 21-23° C.), and the productgradually came out of solution. The distillation was stopped at thispoint, and more ethanol (50 mL) was added. The mixture was warmed (hotwater bath at 50° C.) to 40° C. to dissolve all the solid, and water (90mL) was added slowly via a dropping funnel. The solution was stirredslowly at room temperature (20° C.) overnight (15 hours), by which timesome product had crystallised out. The mixture was cooled to −5° C.(ice/methanol bath) and stirred at this temperature for 20 minutesbefore collecting the pale yellow solid by filtration. The solid waswashed with an ethanol/water mixture (42 mL EtOH, 8 mL H₂O), and suctiondried for 30 minutes before drying to constant weight in the vacuum oven(40° C., 72 hours). The mass of crude product obtained was 47.42 g(149.9 mmol, 60%). Ethanol (160 mL, 8 vols) was added to the crudeproduct (20.00 g, 63.22 mmol, 1.0 eq). The mixture was stirred undernitrogen and warmed to 40° C. using a hot water bath. On reaching thistemperature, all of the solid had dissolved to give a clear, yellowsolution. Water (60 mL, 3 vols) was added dropwise over a period of 10minutes, whilst the internal temperature was maintained in the range38-41° C. The water bath was removed, and the solution was allowed tocool to 25° C. over 40 minutes, by which time crystallisation had begun.The mixture was cooled to −5° C. over 10 minutes, then held at thistemperature for a further 10 minutes. The pale yellow solid wascollected by filtration, suction dried for 10 minutes, then dried toconstant weight in a vacuum oven (40° C., 15 hours). The mass ofsub-title compound obtained was 18.51 g (58.51 mmol, 93% (from the crudeproduct)).

(b)(2-{7-[3-(4-Cyanoanilino)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-ethyl)carbamicacid tert-butyl ester

To the solution of[2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamic acid tert-butylester generated in Example 3 (Alternative III) above (assumed 24.15 g,1.0 mol eq., 1.0 wt./vol.) in a mixture of toluene (approx. 100 mL),ethanol (approx. 200 mL) and water (approx. 14 mL), was added anhydrouspotassium carbonate (18.58 g, 1.5 mol eq.). Solid3-(4-cyanoanilino)propyl-4-benzenesulfonate (28.17 g, 1.0 mol eq., seestep (a) above) was added and the combined mixture was heated to 70° C.for six hours. The reaction was monitored by TLC using a silica platewith mobile phase X:DCM 1:1 v/v (in which X ischloroform:methanol:concentrated ammonia 80:18:2 v/v). Visualisation wasby UV light (254 nm) and by staining with aqueous potassiumpermanganate. This showed the complete disappearance of startingmaterial and the appearance of the title compound. The reaction mixturewas cooled, and the solvent was concentrated in vacuo. The residue waspartitioned between toluene (200 mL) and water (200 mL). The layers wereseparated, and the organic phase was concentrated in vacuo to afford ayellow solid (38.6 g). This was dissolved in iso-propanol (190 mL, 5.0rel. vol.) at 60° C., and the hot solution was filtered. The filtratewas stirred, and left to cool to room temperature. A white solidcrystallised. The mixture was cooled from room temperature toapproximately 8° C. The product was collected by filtration and waswashed with iso-propanol (50 mL, 2.0 vol.). The damp product was driedin vacuo at 40° C. to constant weight to give the title compound as awhite crystalline solid (30.96 g, 81%).

m.p. 113.5° C.

¹H-NMR (400 MHz, CD₃OD) δ 1.40 (9H, s), 1.81-1.90 (2H, m), 2.35-2.54(8H, m), 2.93 (4H, t) 3.18-3.27 (4H, m), 3.87 (2H, bs), 6.66 (2H, d),7.39 (2H, d)

MS: m/z =(MH⁺, 430)

Example 5 tert-Butyl2-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamateAlternative I

iso-Propanol (5 mL) and water (0.5 mL) were added to[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)ethyl]carbamic acidtert-butyl ester (see Example 3 (Alternative I) above; 0.43 g, 1.6 mmol)and 4-[(2S)-oxiranylmethoxy]benzonitrile (0.280 g, 1.6 mmol; seePreparation D above) was added. The mixture was heated at 66° C. for 19hours (reaction was complete in 2 hours). The solvent was evaporated todryness under reduced pressure to give the title compound as anoff-white solid (0.71 g, 100%).

¹H-NMR (300 MHz, CDCl₃) δ 1.41 (9H, s), 2.3-2.75 (6H, m), 2.75-3.0 (5H,m), 3.1-3.38 (3H, m), 3.88 (2H, s), 3.95-4.19 (3H, m), 5.85 (1H, bs),6.99 (2H, d), 7.6 (2H, d).

¹H-NMR (300 MHz, DMSO-D₆) δ 1.35 (9H, s), 2.12-2.59 (7H, m), 2.63-2.78(1H, m), 2.78-2.9 (4H, m), 3.2 (2H, q), 3.78 (2H, m), 4-4.1 (2H, m),4.12-4.19 (1H, m), 5.3 (1H, bs), 6.61 (1H, t), 7.15 (2H, d), 7.76 (2H,d).

MS: m/z=447 (MH⁺)

Alternative II

The solution of [2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamicacid tert-butyl ester generated in Example 3 (Alternative II) above(assumed 154.85 g, 1.0 mol eq, 1.0 wt/vol) in a mixture of toluene(approx 640 mL), ethanol (approx 1280 mL) and water (approx 130 mL), wasbasified with aqueous sodium hydroxide (10M, 51 mL, 0.9 mol eq.). Solid4-[(2S)-oxiranylmethoxy]benzonitrile (99.80 g, 1.0 mol eq.; seePreparation D above) was added and the combined mixture was heated to70° C. for four hours. The reaction was monitored by TLC using a silicaplate with mobile phase X:DCM 1:1 v/v (in which X ischloroform:methanol:concentrated ammonia 80:18:2 v/v). Visualisation wasby UV light (254 nm) and by staining with aqueous potassiumpermanganate. This showed the complete disappearance of startingmaterial and the appearance of the title compound. The reaction mixturewas cooled, filtered through kieselguhr and washed through with ethanol(620 mL, 4.0 vol). This gave a solution of title compound (assumed254.38 g, 100% th, 2.4 L, 1.0 wt/vol for reaction work up). Thissolution was charged into a flask that was set up for reduced pressuredistillation. A graduation line was marked onto the side of this flask.Solvent (1250 mL) was removed at between 50° C. and 35° C., 320 mbar and100 mbar. Then 4-methylpentan-2-ol (1500 mL) was added in order to reachthe graduated line. Solvent (1250 mL) was removed at between 35° C. and80° C., 220 mbar and 40 mbar. More 4-methylpentan-2-ol (1500 mL) wasadded in order to reach the graduated line. Solvent (1250 mL) wasremoved at between 62° C. and 76° C., 100 mbar and 90 mbar. The combinedmixture was cooled to less than 25° C. and aqueous sodium hydroxide (2M,1.27 L, 5.0 vol) was added. The layers were separated and the organiclayer was filtered through kieselguhr to give a clear solution (1.2 L).This solution was charged into a clean flask, which was set up forreduced pressure distillation. Solvent (450. mL) was removed at between52° C. and 55° C., 90 mbar and 35 mbar. Theoretically, the product wasnow left in 2 volumes of 4-methylpentan-2-ol. Di-n-butyl ether (1.27 L,5 vol) was added and the solution was allowed to cool slowly to roomtemperature, which caused a precipitate to form. The mixture was cooledfrom room temperature to approximately 10° C. The product was collectedby filtration and was washed with a pre-mixed solution of di-n-butylether (320 mL, 1.25 vol) and 4-methylpentan-2-ol (130 mL, 0.50 vol). Thedamp product was dried in vacuo at 55° C. to constant weight to give thetitle compound as a white solid (193.6 g, 76%).

m.p. 99-101° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.41 (9H, s), 2.3-2.75 (6H, m), 2.75-3.0 (5H,m), 3.1-3.38(3H, m), 3.88 (2H, s), 3.95-4.19 (3H, m), 5.85 (1H, bs),6.99 (2H, d), 7.6 (2H, d).

Abbreviations

-   API=Abbreviations-   API=atmospheric pressure ionisation (in relation to MS)-   br=broad (in relation to NMR)-   dd=doublet (in relation to NMR)-   DCM=dichloromethane-   dd=doublet of doublets (in relation to NMR)-   DMF=N,N-dimethylformamide-   DMSO=dimethylsulfoxide-   Et=ethyl-   eq.=equivalents-   GC=gas chromatography-   h=hour(s)-   HCl=hydrochloric acid-   HPLC=high performance liquid chromatography-   IMS=industrial methylated spirit-   IPA=iso-propyl alcohol-   KF=Karl-Fischer-   m=multiplet (in relation to NMR)-   Me=methyl-   MeCN=acetonitrile-   min.=minute(s)-   m.p.=melting point-   MS=mass spectroscopy-   Pd/C=palladium on carbon-   q=quartet (in relation to NMR)-   rt=room temperature-   s=singlet (in relation to NMR)-   t=triplet (in relation to NMR)-   TLC=thin layer chromatography-   UV=ultraviolet

Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal,secondary, iso, and tertiary.

1. A process for the preparation of a compound of formula I,

wherein R¹ represents H, an amino protective group or a structuralfragment of formula la,

in which R³ represents H, halo, C₁₋₆ alkyl, —OR⁶, -E-N(R⁷)R⁸ or,together with R⁴, represents ═O; R⁴ represents H, C₁₋₆ alkyl or,together with R³represents ═O; R⁶ represents H, C₁₋₆ alkyl, -E-aryl,-E-Het¹, —C(O)R^(9a), —C(O)OR^(9b) or —C(O)N(R^(10a))R^(10b); R⁷represents H, C₁₋₆ alkyl, -E-aryl, -E-Het¹, —C(O)R^(9a), —C(O)OR^(9b),—S(O)₂R^(9c), —[C(O)]_(p)N(R^(10a))R^(10b) or —C(NH)NH₂; R⁸ representsH, C₁₋₆ alkyl, -E-aryl or —C(O)R^(9d); R^(9a) to R^(9d) independentlyrepresent, at each occurrence, C₁₋₆ alkyl (optionally substituted and/orterminated by one or more substituents selected from halo, aryl andHet²), aryl, Het³, or R^(9a) and R^(9d) independently represent H;R^(10a) and R^(10b) independently represent, at each occurrence, H orC₁₋₆ alkyl (optionally substituted and/or terminated by one or moresubstituents selected from halo, aryl and Het⁴), aryl, Het⁵, or togetherrepresent C₃₋₆ alkylene, optionally interrupted by an O atom; Erepresents, at each occurrence, a direct bond or C₁₋₄ alkylene; prepresents 1 or 2; A represents -G-, -J-N(R¹¹)— or -J-O— (in whichlatter two groups, N(R¹¹)— or O— is attached to the carbon atom bearingR³ and R⁴); B represents -Z-, -Z-N(R¹²)—, —N(R¹²)-Z-, -Z-S(O)_(n)— or-Z-O— (in which latter two groups, Z is attached to the carbon atombearing R³ and R⁴; G represents a direct bond or C₁₋₆ alkylene; Jrepresents C₂₋₆ alkylene; Z represents a direct bond or C₁₋₄ alkylene;R¹¹ and R¹² independently represent H or C₁₋₆ alkyl; n represents 0, 1or 2; R⁵ represents phenyl or pyridyl, both of which groups areoptionally substituted by one or more substituents selected from —OH,cyano, halo, nitro, C₁₋₆ alkyl (optionally terminated by—N(H)C(O)OR^(13a)), C₁₋₆ alkoxy, —N(R^(14a))R^(14b), —C(O)R^(14c),—C(O)OR^(14d), —C(O)N(R^(14e))R^(14f), —N(R^(14g))C(O)R^(14h),—N(R^(14i))C(O)N(R^(14j))R^(14k), —N(R^(14m))S(O)₂R^(13b), —S(O)₂R^(13c)and/or —OS(P)₂R^(13d); R^(13a) to R^(13d) independently represent C₁₋₆alkyl; R^(14a) and R^(14b) independently represent H, C₁₋₆ alkyl ortogether represent C₃₋₆ alkylene, resulting in a four- to seven-memberednitrogen-containing ring; R^(14c) to R^(14m) independently represent Hor C₁₋₆ alkyl; and Het¹ to Het⁵ independently represent, at eachoccurrence, five- to twelve-membered heterocyclic groups containing oneor more heteroatoms selected from oxygen, nitrogen and/or sulfur, whichheterocyclic groups are optionally substituted by one or moresubstituents selected from ═O, —OH, cyano, halo, nitro, C₁₋₆ alkyl, C₁₋₆alkoxy, aryl, aryloxy, —N(R^(15a))R^(15b), —C(O)R^(15c), —C(O)R^(15d),—C(O)N(R^(15e))R^(15f), —N(R^(15g))C(O)R^(15h) and—N(R^(15i))S(O)₂R^(15j); R^(15a) to R^(15i) independently represent C₁₋₆alkyl, aryl or R^(15a) to R^(15i) independently represent H; providedthat: (a) when R⁴ represents H or C₁₋₄ alkyl; and A represents-J-N(R¹¹)— or -J-O—; then B does not represent —N(R¹²)—, —S(O)_(n)—, —O—or —N(R¹²)-Z- (in which latter group —N(R¹²) is attached to the carbonatom bearing R³ and R⁴); (b) when R³ represent OR⁶ or -E-N(R⁷)R⁸ inwhich E represents a direct bond, then: (i) A does not represent adirect bond, -J-N(R¹¹)— or J-O—; and (ii) B does not represent —N(R¹²)—,—S(O)_(n)—, —O— or —N(R¹²)-Z- (in which latter group —N(R¹²) is attachedto the carbon atom bearing R³ and R⁴); and R² represents C₁₋₆ alkyl(optionally substituted and/or terminated by one or more substituentsselected from —OH, halo, cyano, nitro and aryl) or aryl, wherein eacharyl and aryloxy group, unless otherwise specified, is optionallysubstituted by one or more of —OH, cyano, halo, nitro, C₁₋₆ alkyl, C₁₋₆alkoxy, —N(R^(14a))R^(14b), —C(O)R^(14c), —C(O)OR^(14d),—C(O)N(R^(14c))R^(14f), —N(R^(14g))C(O)R^(14h),—N(R^(14m))S(O)R²R^(13b), —S(O)₂R^(13c) and/or —OS(O)₂R^(13d); whichprocess comprises reaction of a compound of formula II,

wherein as defined above, with either: (i) a compound of formula ITT,

wherein R¹⁶ represents unsubstituted C₁₋₄ alkyl, C₁₋₄ perfluoroalkyl orphenyl, which latter group is optionally substituted by one or moresubstituents selected from C₁₋₆ alkyl, halo, nitro and C₁₋₆ alkoxy, andR² is as defined above; or (ii) acrylamide, followed by reaction of theresulting intermediate of formula IV,

wherein R¹ as defined above, with an alcohol of formula R²—OH and anagent that promotes, or agents that in combination promote,rearrangement and oxidation of the compound of formula IV to anintermediate isocyanate, which may then react with the alcohol offormula R²—OH, wherein R² is as defined above. 2-34. (canceled)
 35. Aprocess for the preparation of a compound of formula I, as defined inclaim 1, in which R¹ represents H, which process comprises removal ofthe amino protective group from a corresponding compound of formula I inwhich R¹ represents an amino protective group. 36-77. (canceled)